1.What is M3 leukemia?
A: Acute leukemia can be divided into acute lymphoblastic leukemia and acute myeloid leukemia. M3 leukemia is a type of acute myeloid leukemia. Myeloid cells have a necessary process from stem cells to maturity. Because of the influence of genetics or molecular biology, the cells may develop different cancerous changes at different stages of development. Then, according to cell morphology, acute myeloid leukemia can be divided into eight categories, M0 to M7.
M3 leukemia is a leukocyte differentiation to the early juvenile stage, and then stops differentiating. This leukemia is named acute promyelocytic leukemia.
There is a lack of data from the latest leukemia epidemiological surveys in China. The overall incidence of leukemia in China is estimated to be 4 per 100,000, of which AML accounts for 60-70%. M3 accounts for 15% of acute myeloid leukemia.
2. What is the treatment effect of M3 leukemia?
A: Among acute leukemia, the treatment effect of M3 leukemia is relatively good, with a cure rate of up to 95%, and most patients can survive for a long time.
3.How to choose retinoic acid, arsenic and chemotherapy in the treatment of incipient M3 leukemia?
A: Unlike chemotherapy, retinoic acid is a kind of “induction therapy”, which has the effect of “inducing differentiation”. Retinoic acid encourages myeloid cells that have stalled in differentiation to the promyelocytic stage to continue to “grow” until they mature. This is followed by the natural aging of the cells and their eventual demise.
Arsenicum is a traditional Chinese medicine. It was first used by some Chinese doctors in the northeast of China to treat various leukemias, and was found to be particularly suitable for M3 leukemia. Further research at Ruijin Hospital found that arsenic has the effect of “apoptosis induction”, which can induce the death of cancerous cells.
The reason why retinoic acid + arsenic is particularly effective in the treatment of M3 leukemia is that M3 leukemia is characterized by ectopic chromosome 15 and 17, resulting in the fusion of two special genes, namely PML gene and RARα gene, forming PML-RARα fusion gene. This fusion gene is the root cause of M3 leukemia. No coincidence. Retinoic acid + arsenic can “target” these two specific genes. The target of retinoic acid is the RARα gene, and the target of arsenic is the PML gene. The simultaneous attack of retinoic acid + arsenic can stop the fusion gene from acting up. Therefore, retinoic acid + arsenic was the first “targeted therapy drug”.
Currently, chemotherapy alone has been abandoned, and retinoic acid, arsenic, and chemotherapy are all used in the treatment of M3 leukemia. There are slight differences in treatment regimens at home and abroad. In Western countries, retinoic acid + chemotherapy was mainly used in earlier years.
4.How is the treatment process of M3 leukemia?
A: The treatment of M3 leukemia is divided into 3 stages.
The first stage is induction therapy, mainly with retinoic acid + arsenic and with or without chemotherapy according to the risk stratification. At this point, only 2 things are done, namely normalization of blood and bone marrow to achieve “hematological remission”. However, more attention is paid to whether the fusion gene turns negative or not. Once the induction therapy is effective and the disease is in remission, we enter the second phase, i.e. consolidation therapy, which is mainly retinoic acid + arsenic, with or without chemotherapy. 2 to 3 courses of treatment later, we have to test whether the fusion gene turns negative. If the fusion gene is negative, it means that “molecular remission” is achieved. Some patients achieve molecular remission during the first phase of induction therapy, indicating a high sensitivity to treatment. Only after a negative gene conversion can the patient enter the third phase, maintenance therapy. Maintenance therapy is also administered with retinoic acid + arsenic.
Each stage of M3 leukemia treatment has clear nodes, and if it is not achieved, it cannot move to the next stage.
5. Which patients with initial disease can be treated without chemotherapy?
A: This is a question we are currently looking at. Many diseases can be classified as low-risk, intermediate-risk, or high-risk. Recent studies have concluded that low risk M3 patients may not need chemotherapy, but only retinoic acid + arsenic, either in induction therapy or in the consolidation and maintenance phase. While high-risk patients need retinoic acid + arsenic + chemotherapy.
6.How to distinguish between low, medium and high risk of M3 leukemia?
A: This depends on the test results, and is different from the disease staging as understood by the general public.
Mainly for classical M3 leukemia, i.e. those with chromosome 15 and 17 ectopic, we will go through the blood routine and perform stratification. Those with leukocytes greater than 10,000 are in the high-risk group. If the white blood cells are less than 10,000 and platelets are greater than 40,000, they belong to the low-risk group. Those with white blood cells less than 10,000 and platelets less than 40,000 belong to the intermediate risk group.
7.Is it feasible for some hospitals to treat M3 leukemia with only retinoic acid + chemotherapy or arsenic + chemotherapy?
A: According to the results of our center and international studies, it is more recognized that the combination of retinoic acid + arsenic is more effective.
It has been suggested that retinoic acid + arsenic is like two trump cards in poker, one can be used first and then the other when the situation is critical. And from our study, we found that the relapse rate of M3 leukemia after retinoic acid + arsenic + chemotherapy is lower than retinoic acid + chemotherapy or arsenic + chemotherapy.
8. Is there a risk of early death in M3 induction therapy? What causes of death are included?
A: There are two major unresolved issues in the treatment of M3 leukemia. The first is early death, and the most important cause of death is bleeding, with an incidence of 7-8%, especially in high-risk and very high-risk patients. This is because the onset of action of retinoic acid + arsenic takes 1 week. And the aforementioned patients may experience severe bleeding within two or three days of diagnosis, leading to death.
The second is relapse. This is rare in the low and intermediate risk group and is mostly seen in the high risk group, with an incidence of about 5%. Moreover, relapse is prone to arsenic resistance and poor treatment effect.
9.How to prevent and avoid early death in M3?
A: This is a question that is being explored by doctors all over the world.
For high-risk patients, we can expect that they have a high risk of bleeding death, but still lack effective control methods. It is possible to monitor closely in order to control the bleeding in time to save the patient’s life. Patients who die early have very high white blood cells and it is quite important to control them as soon as possible. Early detection and early intervention of patients can also reduce the risk of death.
10. Do I need to do a bone marrow transplant for first-episode patients? When should I do it?
A: After standard treatment of M3 leukoaraiosis with retinoic acid + arsenic + chemotherapy, most patients can be cured and in principle do not need bone marrow transplantation. Less than 1% of M3 patients are refractory, insensitive to vincristine + arsenic + chemotherapy, with a treatment efficiency of less than 10%. There are also about 20% of patients in the high-risk group who may relapse. For both of these groups, a bone marrow transplant may be required.
For example, after relapse, if the patient is of appropriate age and the fusion gene turns negative after induction therapy, autologous stem cell transplantation can be done. If the fusion gene does not turn negative, i.e. there is always residual lesion, allogeneic stem cell transplantation is needed.
11.How to predict the effect of M3 leukemia treatment?
A: Most typical M3 leukemias are curable, but we found that the effect of retinoic acid + arsenic therapy is generally not satisfactory in atypical M3 leukemias, i.e. the cause is not chromosome 15 and 17 ectopic.
And like typical refractory M3 and relapsed cases, it is more difficult to predict the treatment outcome.
12.To assess the treatment effect of M3, should we look at bone aspiration or genetic testing?
A: Regardless of the stage, both bone aspiration and genetic testing should be done. Since genes are thousands of times more sensitive than bone marrow images. Therefore, the aim of treatment is to see if the fusion gene can be turned negative.
13.When M3 treatment reaches what criteria, it is considered as clinical cure?
A. When the fusion gene turns negative and the maintenance treatment reaches 5 cycles, the clinical treatment is basically finished. In Europe and the United States, it has been proposed that the maintenance treatment can be less or no maintenance treatment, and only the fusion gene can be turned negative as the standard for the end of clinical treatment, which is still under further study.
14.What if M3 relapses?
A: Some patients relapse within a short period of time, that is, during the application of retinoic acid + arsenic, and their treatment after relapse is more difficult. This indicates that the patient may be resistant to retinoic acid + arsenic, and chemotherapy is more often used after relapse.
If the patient has stopped treatment for a long time and relapses again, then he or she may still be sensitive to retinoic acid + arsenic and should still follow the clinical path of induction therapy – consolidation therapy – maintenance therapy.
15.Do intramedullary and extramedullary relapses affect treatment choice?
A: Intramedullary relapses are also known as hematologic relapses. Treatment depends on the timing of the relapse, whether it is a short-term relapse or a relapse after stopping treatment for a long time.
Extramedullary relapses are relapses other than bone marrow, such as central nervous system relapses. Treatment of extramedullary relapse is difficult because retinoic acid + arsenic is difficult to cross the blood-brain barrier. Chemotherapy must be followed up at this point, and stem cell transplantation may also be required. The prognosis for extramedullary relapse is even worse.